The present invention relates to novel indane-like compounds and to formulations containing such indane-like compounds as an active ingredient for pharmaceutical or veterinary use.
Currently there are many drugs available for the treatment of disorders of the central nervous system. Amongst these drugs is a category known as antipsychotics for treating serious mental conditions such as psychosis, including but not limited to schizophrenia and schizophreniform illnesses. The skilled artisan will recognize that these psychotic conditions are characterized by hallucinations, delusions, or grossly disorganized behavior which indicate that the patient suffers from gross impairment in reality testing. Drugs having said antipsychotic activity can be useful for treating a variety of important psychotic disorders. The drugs commercially available for such conditions are often associated with undesirable side effects. There is a need for additional therapeutic choices to control or eliminate the symptoms in the safest and most effective way. Furthermore, patients often do not respond or only partially respond to present drug treatment, and estimates of such partial- or non-responders has varied between 40% and 80% of those treated.
Ever since antipsychotics were introduced it has been observed that patients are liable to suffer from drug-induced extrapyramidal symptoms which include drug-induced Parkinsonism, acute dystonic reactions, akathisia, tardive dyskinesia and tardive dystonia. The Simpson Angus Scale, Barnes Akathisia Rating Scale and Abnormal Involuntary Movement Scale (AIMS) are well known scales for assessing extrapyramidal symptoms. The great majority of drugs available for treatment of schizophrenia are prone to produce these extrapyramidal side effects when used at dosages that yield a beneficial effect on the symptoms of the disease. The severity of adverse events and/or lack of efficacy in a considerable number of patients frequently results in poor compliance or termination of treatment.
Many of the drugs are associated with a sedative effect and may also have an undesirable influence on the affective symptoms of the disease, causing depression. In some instances long term use of the drug leads to irreversible conditions, such as the tardive dyskinesia and tardive dystonia referred to supra.
A widely-used antipsychotic, haloperidol, is one such drug, which has been reported as causing a high incidence of extrapyramidal symptoms and may also cause tardive dyskinesia. More recently, clozapine, one of a large group of heterocyclic antipsychotics, has been introduced with the claim that it is free from extrapyramidal effects. However, the compound was found to cause agranulocytosis in some patients, a condition resulting in a lowered white blood cell count which can be life-threatening, and it may now only be employed under very strict medical observation and supervision.
Therefore, new compounds having antipsychotic activity are highly desired.
The present invention provides a compound of the Formula I: 
R1 is selected from the group consisting of hydrogen, xe2x80x94OR4, xe2x80x94SRS, C1-C3 alkyl, C2-C3 alkenyl, halo, xe2x80x94CN, S(O)m2, xe2x80x94COR4bxe2x80x2, and xe2x80x94OC(O)xe2x80x94R15;
m2 is from 0 to 2;
R2 is selected from the group consisting of C1-C10 alkyl, substituted C1-C10 alkyl, C2-C10 alkenyl, substituted C2-C10 alkenyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
R4 is hydrogen, C1-C3 alkyl;
R5 is hydrogen, C1-C3 alkyl;
R10 is selected from the group consisting of hydrogen, carbonyl, halo, and C1-C3 alkyl;
R11 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R12 is independently selected from the group consisting of hydrogen, C1-C10 alkyl, and aryl;
R13 is independently selected from the group consisting of hydrogen, C1-C10 alkyl, and aryl; or
R12 and R13 together with the nitrogen to which they are attached form a group of the formula II: 
xe2x80x83or
xe2x80x83or IIxe2x80x2 wherein the IIxe2x80x2 group is a group of Formula II which is unsaturated; or
R11 and R12 together with the nitrogen and carbon to which they are bound can join to form a three to six membered ring;
R14 is selected from the group consisting of H, halo, C1-C3 alkyl, S(O)m3 and xe2x80x94OR16;
R15 is C1-C3 alkyl or aryl;
R16 is C1-C3 alkyl;
R17 is independently selected from the group consisting of hydrogen, xe2x80x94OR4xe2x80x2, xe2x80x94SR5xe2x80x2, C1-C3 alkyl, C2-C3 alkenyl, halo, xe2x80x94CN, S(O)m2xe2x80x2, xe2x80x94COR4b, and xe2x80x94OC(O)xe2x80x94R15xe2x80x2;
R4b and R4bxe2x80x2 are each independently selected from hydrogen and C1-C3 alkyl;
R15xe2x80x2 is C1-C3 alkyl or aryl;
m2xe2x80x2 is 0 to 2;
R4xe2x80x2 is hydrogen, C1-C3 alkyl;
R5xe2x80x2 is hydrogen, C1-C3 alkyl;
m2 is 0 to 2;
X is selected from the group consisting of CH2, O, S, NH, carbonyl, and a bond;
nxe2x80x2 is 0 to 2;
mxe2x80x2 is 0 to 2;
m3 is 0 to 2;
n is 0 to 3; or
a pharmaceutically acceptable salt or solvate thereof.
Further, the invention provides a method for treating psychosis comprising administering a compound of Formula I to a mammal in need of such treatment.
Additionally, the present invention provides a method for interacting with a muscarinic receptor comprising administering a compound of Formula I.
Finally, the invention provides a formulation containing a compound of Formula I as an active ingredient.
Further this invention provides compounds of the Formula III 
R1 is selected from the group consisting of hydrogen, xe2x80x94OR4, xe2x80x94SR5, C1-C3 alkyl, C2-C3 alkenyl, halo, xe2x80x94CN, S(O)m2, xe2x80x94COR4bxe2x80x2, and xe2x80x94OC(O)xe2x80x94R15;
m2 is from 0 to 2;
R2 is selected from the group consisting of C1-C10 alkyl, substituted C1-C10 alkyl, C2-C10 alkenyl, substituted C2-C10 alkenyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
R4 is hydrogen, C1-C3 alkyl;
R5 is hydrogen, C1-C3 alkyl;
R10 is selected from the group consisting of hydrogen, carbonyl, halo, and C1-C3 alkyl;
R11 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R12 is independently selected from the group consisting of hydrogen, C1-C10 alkyl, and aryl;
R13 is independently selected from the group consisting of hydrogen, C1-C10 alkyl, and aryl; or
R12 and R13 together with the nitrogen to which they are attached form a group of the formula II: 
xe2x80x83or IIxe2x80x2 wherein the IIxe2x80x2 group is a group of Formula II which is unsaturated; or
R11 and R12 together with the nitrogen and carbon to which they are bound can join to form a three to six membered ring;
R14 is selected from the group consisting of H, halo, C1-C3 alkyl, S(O)m3 and xe2x80x94OR16;
R15 is C1-C3 alkyl or aryl;
R16 is C1-C3 alkyl;
R17 is independently selected from the group consisting of hydrogen, xe2x80x94OR4xe2x80x2, xe2x80x94SR5xe2x80x2, C1-C3 alkyl, C2-C3 alkenyl, halo, xe2x80x94CN, S(O)m2xe2x80x2, xe2x80x94COR4b, and xe2x80x94OC(O)xe2x80x94R15xe2x80x2;
R4b and R4bxe2x80x2 are each independently selected from hydrogen and C1-C3 alkyl;
R15xe2x80x2 is C1-C3 alkyl or aryl;
m2xe2x80x2 is 0 to 2;
R4xe2x80x2 is hydrogen, C1-C3 alkyl;
R5, is hydrogen, C1-C3 alkyl;
m2 is 0 to 2;
X is selected from the group consisting of CH2, O, S, NH, carbonyl, and a bond;
nxe2x80x2 is 0 to 2;
mxe2x80x2 is 0 to 2;
m3 is 0 to 2;
n is 0 to 3; or
a pharmaceutically acceptable salt or solvate thereof.
Additionally, this invention provides a formulation comprising a compound of Formula III and one or more pharmaceutically acceptable excipients or carriers therefor.
Also included is a method for treating a condition associated with the modulation of a muscarinic receptor comprising administering an effective amount of a compound of Formula III to a mammal in need of such treatment.
Additionally, provided is a compound of Formula IV 
R21 and R22 are selected from H and O;
R20 is selected from amine protecting groups;
R1xe2x80x2 is selected from the group consisting of xe2x80x94OR4, xe2x80x94SR5, C1-C3 alkyl, C2-C3 alkenyl, halo, xe2x80x94CN, S(O)m2, xe2x80x94COR4bxe2x80x2, and xe2x80x94OC(C)xe2x80x94R15;
m2 is 0 to 2;
R4 and R4bxe2x80x2 are each independently selected from hydrogen and C1-C3 alkyl;
R5 is selected from hydrogen and C1-C3 alkyl;
R15 is C1-C3 alkyl or aryl; or
a pharmaceutically acceptable salt or solvate thereof.
The term xe2x80x9ctreatingxe2x80x9d as used herein includes prophylaxis of the named physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established.
The substituent of Formula II can be from a 3-member to 8 member ring. The substituent of Formula IIxe2x80x2 is unsaturated. Formula IIxe2x80x2 is optionally aromatic, but is in no way required to be aromatic. It may be preferred that Formula IIxe2x80x2 contains from one to two double bonds.
The term xe2x80x9cinteracting with a muscarinic receptorxe2x80x9d refers to a compound acting as a muscarinic receptor agonist, antagonist, or partial agonist. Most preferably, the compounds of this invention will act as an agonist of a muscarinic receptor. It is especially preferred that a compound of this invention will selectively interact with a m4 muscarinic receptor subtype. Further it is particularly preferred that a compound of this invention will act as a selective m4 muscarinic receptor agonist.
The terms xe2x80x9cC1-Cm alkylxe2x80x9d wherein m=2-10, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms. For example, typical C1-C6 alkyl groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
The term xe2x80x9csubstituted C1-Cm alkylxe2x80x9d refers to an alkyl group which is substituted with from one to five selected from the group consisting of C2-C6 alkenyl, halo, xe2x80x94CF3, xe2x80x94OR4a, xe2x80x94SR5a, CO2R6a, halo, C3-C8 cycloalkyl, substituted C4-C8 cycloalkyl, and xe2x80x94CN; wherein 4a, 5a, and 6a are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, aryl and substituted aryl.
The term xe2x80x9ccarbonylxe2x80x9d,has the meaning commonly attributed to the term by the skilled artisan. For example, =O.
The terms xe2x80x9cC2-Cn alkenylxe2x80x9d wherein n=3-10, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to 10 carbon atoms and at least one double bond. The groups can be branched or straight chain. Examples of such groups include 1-propenyl, 2-propenyl (xe2x80x94CH2xe2x80x94CHxe2x95x90CH2), 1-butenyl (xe2x80x94CHxe2x95x90CHCH2CH3), 1,3-butadienyl (xe2x80x94CHxe2x95x90CHCHxe2x95x90CH2), hexenyl, pentenyl, and the like.
The terms xe2x80x9chalidexe2x80x9d, xe2x80x9chalogenxe2x80x9d, and xe2x80x9chaloxe2x80x9d include fluorine, chlorine, bromine, and iodine. The preferred halogen is chlorine.
The term xe2x80x9cC3-Cn cycloalkylxe2x80x9d wherein n=4-8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Ecycloheptyl, cyclooctyl, and the like.
The term xe2x80x9chererocyclicxe2x80x9d refers to a heterocyclic ring having from four to eight members and from one to three non-carbon atoms selected from the group consisting of N, O, and S; or a combination thereof, and which heteroaryl group is optionally fused with a phenyl group.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d refers to a heterocyclic group which may be substituted with from one to three substituents selected from the group consisting of halogen(s), xe2x80x94CF3, NO2, xe2x80x94CN, C1-15-alkyl, C2-5alkenyl, C2-5-alkynyl, xe2x80x94COR6a, xe2x80x94OR4a, xe2x80x94SR5a, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, substituted C3-C8 cycloalkyl, substituted C5-C8 cycloalkenyl, and aryl; wherein 4a, 5a, and 6a are each independently selected from hydrogen, xe2x80x94CF3, C1-C3 alkyl, aryl, and xe2x80x94C1-C3 alkyl-aryl.
As used herein the term xe2x80x9camine protecting groupxe2x80x9d refers to protecting groups such as those discussed in Theodora W. Greene, Protective Groups in Organic Synthesis, (Wiley, 1981) pp. 218-287. Especially preferred amine protecting groups are carbamates. One particularly preferred amine protecting group is BOC.
The term xe2x80x9csubstituted(C5-Cn) cycloalkylxe2x80x9d refers to a cycloalkyl group as described supra wherein the cycloalkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, NO2, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, C2-C6 alkenyl, C3-C8 cycloalkyl-(C1-C3)alkyl, C5-C8 cycloalkenyl, C5-C8 cycloalkenyl-(C1-C3)alkyl, COR5a, C1-C10 alkanoyl, C7-C16 arylalkyl, CO2R5a, (C1-C6 alkyl)mamino, xe2x80x94SR5a, and OR5a; wherein 5a is selected from hydrogen and C1-C3 alkyl; m is from one to two.
The term xe2x80x9cC3-C8 cycloalkyl-(C1-C3)alkylxe2x80x9d represents a linear alkyl group substituted at a terminal carbon with a C3-C8 cycloalkyl group. Typical cycloalkylalkyl groups include cyclohexylethyl, cyclohexylmethyl, 3-cyclopentylpropyl, and the like.
The term xe2x80x9cC5-C8 cycloalkenylxe2x80x9d represents an olefinically unsaturated ring having five to eight carbon atoms, eg., cyclohexadienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like. The cycloalkenyl group may be substituted with from one to four substituents selected from the group consisting of hydrogen, C1-C6 alkyl, NO2, halo, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, C2-C6 alkenyl, (C1-C6 alkyl)amino, COR5, C1-C10 alkanoyl, OR5, CO2R5, xe2x80x94SR5, and C7-C16 arylalkyl.
The term xe2x80x9cC5-C8 cycloalkenyl-(C1-C3)alkylxe2x80x9d represents a linear C1-C3 alkyl group substituted at a terminal carbon with a C5-C8 alkenyl group.
As used herein the term xe2x80x9ccarboxylxe2x80x9d refers to a substituent having the common meaning understood by the skilled artisan, wherein the point of attachment may be through the carbon or oxygen atom of the group.
As used herein the term xe2x80x9carylxe2x80x9d means an organic radical derived from an aromatic hydrocarbon by the removal of one atom. For example, the term includes, but is in no way limited to biphenyl, phenyl or naphthyl. The term xe2x80x9carylxe2x80x9d refers to hydrocarbon aryl groups. Most preferably, aryl refers to C6-C10 aryl, wherein the aryl ring system, including any alkyl substitutions, comprises from 6 to 10 carbon atoms; e.g., phenyl, 3,3-dimethylphenyl, naphthyl, and the like. The aryl radical may be substituted by one or two C1-C6 straight or branched alkyl. The aryl group may be fused with a heteroaryl or heterocyclic.
xe2x80x9cSubstituted arylxe2x80x9d refers to an aryl group which may be substituted with from one to three substituents selected from the group consisting of halogen(s), xe2x80x94CF3, NO2, xe2x80x94CN, C1-15-alkyl, C2-5-alkenyl, C2-5-alkynyl, xe2x80x94COR6a, OR4a, xe2x80x94SR5a, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, substituted C3-C8 cycloalkyl, substituted C5-C8 cycloalkenyl, and aryl; wherein 4a, 5a, and 6a are each independently selected from hydrogen, xe2x80x94CF3, C1-C3 alkyl, aryl, and xe2x80x94C1-C3 alkyl-aryl. The substituents may be located at any available position on the ring, provided that there is not more than one substituent selected from the group consisting of aryl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and substituted C5-C8 cycloalkenyl.
As used herein, the phrase xe2x80x9cheteroarylxe2x80x9d means an aryl group containing from one to three N, O or S atom(s) or a combination thereof, and which heteroaryl group is optionally fused with a phenyl group. The phrase xe2x80x9cheteroarylxe2x80x9d includes, but is not limited to, 5-membered heteroaryls having one hetero atom (e.g. thiophenes, pyrroles, furans); 5-membered heteraryls having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteraryls having three heteroatoms (e.g. triazoles, thiadiazoles); 5-membered heteraryls having 3-heteroatoms; 6-membered heteroaryls with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heteraryls with two heteroatoms (e.g. pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heteroaryls with three heteroatoms (e.g. 1,3,5-triazine); and 6-member heteroaryls with four heteroatoms. Particularly preferred are benzothiophenes, pyridines, and furans. Most preferredly, the heteroaryl group is a four to eight membered ring.
The term xe2x80x9csubstituted heteroarylxe2x80x9d refers to a heteroaryl group which is substituted at carbon or nitrogen atom(s) with C1-6-alkyl, xe2x80x94CF3, phenyl, benzyl, substituted aryl or thienyl, or a carbon atom in the heteroaryl group together with an oxygen atom form a carbonyl group. Such substituted heteroaryl may optionally be fused with a phenyl group.
The term xe2x80x9cC7-C16 arylalkylxe2x80x9d represents an aryl-(C1-C10)alkyl substituent wherein the alkyl group is linear, such as but not limited to, benzyl, phenethyl, 3-phenylpropyl, or phenyl-t-butyl; or branched. The aryl alkyl moitety is attached to the parent nucleus via the alkyl group.
The term xe2x80x9corganic solventxe2x80x9d includes solvents containing carbon, such as halogenated hydrocarbons, ether, toluene, xylene, benzene, and tetrahydrofuran.
The term xe2x80x9cagitatexe2x80x9d includes such techniques as stirring, centrifugation, mixing, and other similar methods.
The term xe2x80x9cligandxe2x80x9d refers to compounds that are bound by the designated receptor. Compounds useful as ligands may be used to occupy the stated receptor site or may act as a selective agonist at the stated receptor site.
The abbreviations used herein have their accepted meaning, unless stated otherwise. Such accepted meaning shall be the meaning attributed to such term by the skilled artisan or the American Chemical Society.
The terms xe2x80x9cMeOxe2x80x9d and xe2x80x9cEtOxe2x80x9d refer to methoxy and ethoxy substituents which are bound to the parent molecule through the oxygen.
A method for generating the indane scaffold used in this invention for compound forming purposes comprises the following sequential steps:
1. Nitration of indanone starting yields nitroindanone which is then separated from minor component byproducts.
2. The product of step 1 is reduced to give the corresponding alcohol.
3. The product of step 2 is then subjected to an acid catalyzed dehydration to give the corresponding indene.
4. The double bond of the product of step 3 is oxidized to give the epoxide.
5. The product epoxide 4 is then reacted with ammonium hydroxide to give the amino alcohol.
6. The amino alcohol of step 5 is protected with a conventional protecting group.
The preceding method of indane scaffold preparation is further illustrated by the following reaction scheme: 
The formation of indane compounds in these libraries is accomplished using polymer bound reaction schemes generally described as follows:
A) A polymer bearing a carboxylic acid functionality is coupled with the protected indane of the following formula: 
B) The reactants of step (A) are coupled;
C) The product of step (B) is deprotected resulting in an amine functional indane bound to a resin support;
D) The product of step (C) is acylated to attach a first diverse group, E1+;
E) The product of step (D) is reduced to give the corresponding aniline;
F) The product of step (E) is again acylated to attach a second diverse group, E2+;
G) Cleavage with a base of the product of step (E) from the polymer results in the formation of the product characterized by the formula: 
where E1+ and E2+ are any electrophile. 
The process steps, more fully described below in the Preparation Section, are illustrated by the following reaction Scheme IA: 
Multiple simultaneous synthesis may be performed by a variety of apparatus, such as that shown for multiple simultaneous synthesis U.S. Pat. No. 5,324,483; the disclosure of which is incorporated herein by reference.
The compounds of this invention can be prepared using the following general techniques. The skilled artisan will appreciate that there are alternative methods to obtain the desired compounds claimed herein. 
As illustrated by Scheme I, 1 which is commercially available or may be prepared by the skilled artisan using known methods, is dissolved in a mixture of pyridine, 4-dimethylaminopyridine and an inert organic solvent, wherein preferred inert organic solvents include but are not limited to solvents such as THF or CH2Cl2, as acetyl chlorideis added. The mixture may be treated with cold water and the organic layer separated. The organic solution is washed, the organic layer dried, and the solvent evaporated to give 2. A solution of 2 in THF or anther appropriate solvent is treated with a stream of dry HCl. The solution is treated with most preferredly cold saturated sodium bicarbonate, the organic phase was washed, dried and the solvent evaporated to give 3. A solution of 3 in a mixture of pyridine, 4-dimethylaminopyridine, and CH2Cl2 is treated with a solution of an arylsulfonyl chloride and the reaction stirred. The reaction is most preferredly poured into ice-water, the organic layer separated and consecutively washed. Preferred washes are with 1 N HCl and brine. The organics are dried and the solvent evaporated to give 14. A solution of 14 is treated with SnCl2-2 H2O. The reaction mixture is preferredly poured into ice-water, the reaction made basic, and the mixture extracted. The organic extracts are washed, the solution dried, and the solvent evaporated 15. Alternatively, a solution of 14 in EtOAc or THF is treated with H2 (about 60 psi) in the presence of a catalyst. Preferred catalysts are chosen from but not limited to the group consisting of PtO2, Rainey-Ni, and Pd-C. The catalyst is removed and the solvent evaporated to give 15. A solution of 15 is treated with a solution of a chloroalkylene dialkylammonium chloride. It is noted here that the artisan should recognize that other reagents analagous to chloroalkylidene dialkylanmonium chloride can also provide the desired compounds. The reaction was preferredly poured into ice-water, the organic layer separated and consecutively washed. Preferred washes are with saturated sodium bicarbonate and brine. The organics are dried and the solvent evaporated to give 18. A solution of 18 in base is stirred. The reaction mixture is preferredly poured into ice-water and extracted. The organic extracts are washed, dried, and the solvent evaporated to give the desired compound of this invention. 
As illustrated by Scheme II, compounds of this invention can be prepared by a solution of a benzamide being treated with NaH and preferredly, the reaction mixture is stirred until gas evolution ceased. 1,2-Epoxy-6-nitroindane is added. Preferredly the 1,2-epoxy-6-nitroindane is added at about 60 C and stirred. The reaction is preferredly poured into ice-water and extracted. The organic extracts are washed, dried, and the solvent evaporated. The residue is chromatographed to obtain 17. A solution of 17 in a mixture of pyridine, 4-dimethylaminopyridine and an inert organic solvent, for example but not limited to solvents such as THF or CH2Cl2, as acetyl chloride is added. The reaction is preferredly treated with cold water and the organic layer separated. The organic solution is washed, dried, and the solvent evaporated to give 14. Processing of 14 as in Scheme I provides the desired compounds of this invention. 
As illustrated by Scheme III, certain compounds of this invention can be prepared by a mixture of 6-nitroindan-1-one and a catalyst, which is preferredly, but not limited to one chosen from PtO2, Rainey-Ni, and Pd-C in EtOH, is treated with hydrogen. The catalyst is removed and the solvent evaporated to give 8. A solution of 8 in a mixture of pyridine, 4-dimethylaminopyridine, and CH2Cl2 is treated with a solution of a chloroalkylidene dialkylarrmonium chloride and the reaction mixture is preferredly stirred. It is noted here that the artisan should recognize that other reagents analagous to chloroalkylidene dialkylammonium chloride can also provide the desired compounds. The reaction is preferredly poured into ice-water, the organic layer separated and consecutively washed. Preferred washes are with saturated sodium bicarbonate and brine. The organics are dried and the solvent evaporated to give 12. A solution of 12 in a mixture of lower alcohol and NH3 is treated with hydrogen in the presence of a catalyst which is most preferredly, but not limited to, either Pd-C-sulfided or Pt-C sulfided. The catalyst is removed and the solvent evaporated to give 13. A solution of 13 in a mixture of pyridine, 4-dimethylaminopyridine, and CH2Cl2 is treated with a solution of an arylsulfonyl chloride. The reaction is preferredly poured into ice-water, the organic layer separated and consecutively washed. Preferred washes are with saturated sodium bicarbonate and brine. The organics are dried and the solvent evaporated to give the desired compound of this invention. 
Protection of the 3-amino group of compound 5, preferably as a carbamate such as t-butyl carbamate, under standard conditions1 provided compound 1 (also referred to as 6 supra.). Other similar protecting groups can be utilized in place of t-butyl carbamate. Carbamates are particularly preferred protecting groups for the synthesis described by Step 1.
1 Greene and Wuts, Protecting Groups in Organic Chemistry, 
Step 2.
Reduction of the nitro group may be accomplished using reagents such as SnCl2 NaBH4, or more preferably using metal-catalyzed hydrogenation.2 Most preferably, Pd/C was used in EtOH at 50 psi and ambient temperature.
2 Rylander, Hydrogenation 
Step 3.
The amidine functionality of compounds 57-76 may be prepared from the amine by a variety of methods using reagents such as Gold""s reagent. Most preferably the dimethyl amidine was prepared using N,N-dimethylformamide dimethyl acetal under standard conditions.3 
3 Patel amidine series and Meyers paper and ref. 4. 
Step 4.
The amidine may be exchanged in the presence of higher boiling amines such as pyrollidine, piperidine, morpholine, or benzyl amine to provide compounds 6-56 and 77-105.4 
4 Transamidination reaction references. 
Step 5.
The t-butyl carbamate protecting group was removed under standard conditions (ref 1) using cold trifluoroacetic acid.
Step 6.
The trifluoroacetate salt of the amine was reacted with a variety of acid chlorides in the presence of a base such as triethylamine at xe2x88x9210xc2x0 C. to ambient temperature in a solvent such as methylene chloride to provide compounds VII.
Step 7.
The alcohol group of compounds 5-105 may be acylated or alkylated with reagents such as acetic anhydride in the presence of a base such as triethylamine.
The compounds of this invention can form acid addition salts with a wide variety of inorganic and organic acids. Typical acids which can be used include sulfuric, hydrochloric, hydrobromic, phosphoric, hypophosphoric, hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric, cinnamic, benzoic, ascorbic, mandelic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and the like. The pharmaceutically acceptable acid addition salts of the compounds of this invention are especially preferred.
The compounds of the present invention are useful for modulating or blocking the M-1 receptor and can be useful for modulating or blocking a serotonin receptor. Certain of the present compounds are preferred for that use. Preferred compounds and embodiments of this invention are those having the following characteristics. The following preferred characteristics may be independently combined to provide further preferred embodiments of this invention:
A) R3 is aryl;
B) R1 is hydrogen;
C) R1 is xe2x80x94OH;
D) R3 is substituted phenyl having 3,4-dichloro substituents;
E) R2 is substituted phenyl having 3,4-dichloro or meta trifluoromethyl substituents;
F) n is one;
G) the indane ring is saturated;
H) R3 is bicycloaryl;
I) R3 is substituted phenyl having a meta NO2 substituent;
J) R3 is C1-C4 alkyl;
K) R3 is substituted C1-C6 alkyl wherein the terminal carbon of the alkyl chain is substituted with CO2R4 wherein R4 is hydrogen, methyl, or ethyl;
L) R1 is OH, n is 1 and the OH group is located at the 2 position of the ring;
M) a compound of this invention is used for treating psychosis;
N) A compound of Formula I: 
O) n is 1;
P) R2 is substituted phenyl;
Q) A compound of Formula 111;
R) A compound of Formula IV, wherein R20 is a carbamate;
S) A compound of Formula I wherein R12 and R13 are independently C1-C3 alkyl;
T) A compound of Formula I wherein R10 is hydrogen and R1 is OH;
U) A compound of Formula I for treating a condition associated with modulation of an M4 muscarinic subtype receptor;
V) A compound of Formula I which acts as a muscarinic receptor agonist.
Further, the present invention contemplates both the cis and trans stereoisomers of the compounds of Formula I. The trans configuration is preferred.
The present invention contemplates racemic mixtures as well as the substantially pure enantiomers of the compounds of Formula I. The term xe2x80x9cenantiomerxe2x80x9d is used herein as commonly used in organic chemistry to denote a compound which rotates the plane of polarization. Thus, the xe2x80x9cxe2x88x92 enantiomerxe2x80x9d rotates the plane of polarized light to the left, and contemplates the levorotary compound of Formula I. The + and xe2x88x92 enantiomers can be isolated using classical resolution techniques. One particularly useful reference which describes such methods is JACQUES et. al. ENANTIOMERS, RACEMATES, AND RESOLUTIONS (John Wiley and Sons 1981). Appropriate resolution methods include direct crystallization, entrainment, and crystallization by optically active solvents. Chrisey, L. A. Heterocycles, 267, 30 (1990). A preferred resolution method is crystallization by an optically active acid or by chiral synthesis using the method of A. I. Meyers. Loewe, M. F. et al., Tetrahedron Letters, 3291, 26 (1985), Meyers, A. I. et al., J. Am. Chem. Soc. 4778, 110 (1988). Preferred optically active acids include camphorsulfonic and derivatives of tartaric acid.
The compounds of the present invention are known to form hydrates and solvates with appropriate solvents. Preferred solvents for the preparation of solvate forms include water, alcohols, tetrahydrofuran, DMF, and DMSO. Preferred alcohols are methanol and ethanol. Other appropriate solvents may be selected based on the size of the solvent molecule. Small solvent molecules are preferred to facilitate the corresponding solvate formation. The solvate or hydrate is typically formed in the course of recrystallization or in the course of salt formation. One useful reference concerning solvates is Sykes, Peter, A Guidebook to Mechanism in Organic Chemistry, 56+, 6th Ed (1986, John Wiley and Sons, New York). As used herein, the term xe2x80x9csolvatexe2x80x9d includes hydrate forms, such as monohydrates and dihydrates.
The column chromatography procedures used standard flash chromotagraphy techniques. One well-known reference describing appropriate flash chromotagraphy techniques is Still, W. C. Kahn, and Mitra, J. Org. Chem. 1978, 43, 2932. Fractions containing product were generally evaporated under reduced vacuum to provide the product.
Optical rotations were obtained using methanol, pyridine, or other suitable solvent.
The hydrochloride salt of the particular compound was prepared by placing the free base into diethyl ether. While stirring this ether solution, a solution of HCl in diethyl ether was added dropwise until the solution became acidic. Alternatively, the ether solution was treated with dry HCl gas.
The maleate salt of the particular compound was prepared by placing the free base in ethyl acetate and treating with maleic acid. The precipitate formed was filtered and dried to provide the corresponding maleate salt of the free base.
As used herein the term xe2x80x9cmalfunctioning of the muscarinic cholinergic systemxe2x80x9d shall have the meaning accepted by the skilled artisan. For example the term shall refer to, but is not in any way limited to, conditions such as glaucoma, psychosis, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy, and gastrointestinal motility disorders. Other such conditions include Alzheimer""s Disease and incontinence.
The pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of 3H-Oxotremorine-M (3H-Oxo). Birdsdall N. J. M., Hulme E. C., and Burgen A. S. V. (1980). xe2x80x9cThe Character of Muscarinic Receptors in Different Regions of the Rat Brainxe2x80x9d. Proc. Roy. Soc. London (Series B) 207,1.
3H-Oxo labels muscarinic receptor in the CNS (with a preference for agonist domains of the receptors). Three different sites are labeled by 3H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.
The inhibitory effects of compounds on 3H-oxo binding reflects the affinity for muscarinic acetylcholine receptors.
All preparations are performed at 0-4xc2x0 C. unless otherwise indicated. Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenized for 5-10 s in 10 mL 20 nM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 10 mL of buffer and the combined suspension centrifuged for 15 min. at 40,000xc3x97g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2xc3x9710 mL of buffer and centrifuged for 10 min. at 40,000xc3x97g.
The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 mL per g of original tissue) and used for binding assay. Aliquots of 0.5 mL is added 25 xcexcL of test solution and 25 xcexcL of 3H-Oxotremorine (1.0 nM, final concentration) mixed and incubated for 30 min. at 25xc2x0 C. Non-specific binding is determined in triplicate using arecoline (1 xcexcg/mL, final concentration) as the test substance. After incubation samples are added 5 mL of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 mL of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.
Test substances are dissolved in 10 mL water (if necessary heated on a steam-bath for less than 5 min.) at a concentration of 2.2 mg/mL. 25-75% inhibition of specific binding must be obtained before calculation of IC50. The test value will be given as IC50 (the concentration (nM) of the test substance which inhibits the specific binding of 3H-oxo by 50%).
IC50=(applied test substance concentration) x(Cx/Coxe2x88x92Cx)nM where Co is specific binding in control assays and Cx is the specific binding in the test assay. (The calculations assume normal mass-action kinetics).
Furthermore the pharmacological properties of the compounds of the invention can also be illustrated by determining their capability to inhibit 3HPRZ (pirenzepine, [N-methyl-3H]) binding to rat cerebral cortex membranes.
Pirenzepine binds selectively to subtype of muscarinic receptors. Historically the type is named the M1-site, whereas pirenzepine sensitive site would be more appropriate. Although selective for M1-sites pirenzepine also interact with M2-sites.
All preparations are performed at 0-4xc2x0 C. unless otherwise indicated. Fresh cortex (0.1-1 9) from male Wistar rats (150-200 g) is homogenized for 5-10 s in 10 mL 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 2xc3x9710 mL of buffer and the combined suspension centrifuged for 15 min. at 40,000xc3x97g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 3xc3x9710 mL of buffer and centrifuged for 10 min. at 40,000xc3x97g.
The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 mL per g of original tissue) and used for binding assay. Aliquots of 0.5 mL is added 20 xcexcL of test solution and 25 xcexcL of 3HPRZ (1.0 nM, final conc.), mixed and incubated for 60 min. at 20xc2x0 C. Non-specific binding is determined in triplicate using atropine (1.0 xcexcg/mL, final conc.) as the test substance. After incubation samples are added 5 mL of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 mL of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.
Test substances are dissolved in 10 mL water, at a concentration of 0.22 mg/mL. 25-75% inhibition of specific binding must be obtained before calculation of IC50.
The test value will be given as ICSO (the concentration (nM) of the test substance which inhibits the specific binding of 3HPRZ by 50%).
IC50=(applied test substance concentration) x(Cx/Coxe2x88x92Cx)nM where Co is specific binding in control assays and Cx is the specific binding in the test assay. (The calculations assume normal mass-action kinetics).
Compounds of this invention showed particularly desirable activity using the muscarinic receptor assays. Most compounds were effective at an IC50 concentration of less than 10 xcexcmolar (no atropine). The muscarinic effect was confirmed by determining if the effect was blocked by atropine.
Cyclic AMP Accumulation in Pertussis Toxin-Treated CHO m4 Cells.
CHO K1 cells transfected with human m4 receptors were grown to near confluency in T-150 flasks using Dulbecco""s Modified Eagle Medium (DMEM) containing 10% fetal bovine serum. Cells were detached with 0.05% trypsin, 0.53 mm EDTA, and were suspended in medium containing 100 ng/ml pertussis toxin. Cells were plated at 30,000 cells per well into 96 well plates. Eighteen to twenty hours later the medium was removed and the cells were washed with serum-free medium. Attached cells were incubated at 37xc2x0 C. for one hour after addition of 100 ml of serum free DMEM containing 1 mM 3-isobutyl-1-methylxanthine and 1 mM forskolin plus or minus drugs being tested. Incubations were terminated with 200 ml per well of serum free DMEM containing 0.3% triton-X-100. After stopping incubations the plates were allowed to sit for 20 minutes to extract cAMP and samples were then diluted 2.5-fold and were assayed using the scintillation proximity assay of Amersham (Arlington Heights, Ill).
Representative results from the M4 assay are as follows:
Stimulation of cyclic AMP production in CHO-m4cells.
The antipsychotic activity of the presently claimed compounds can be demonstrated in models using well-established procedures. For example the compounds are studied to determine if they antagonize apomorphine-induced climbing behavioral and hypothermia in mice (Moore, N. A. et al. Psychopharmacology 94 (2), 263-266 (1988), and 96, 539 (1988)) which measures the ability of the compound to prevent the disruption of climbing response produced by 24 hour pre-treatment with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), a dopamine receptor inactivating agent (Meller et al. Central D1 dopamine receptors, Plenum Press, 1988) and/or inhibite a conditioned avoidance response in rats (ED50 4-7 mg/kg).
The conflict procedure used is based on the method of Geller and Seifter, Psychopharmacolopia 1: 482-492, (1960). Rats are trained on a multiple schedule consisting of three components. Individual components are as follows: 1) for 9 minutes, lever pressing was reinforced on a variable interval 30 second schedule (VI 30, reward). This period is signaled by illumination of the houselight alone. 2) During the following 3-minute period, lever presses are recorded but had no programmed consequence (time-out). 3) Lever pressing is reinforced according to a fixed ratio 10 second food presentation (FR10) for 3 minutes; however, each reinforced response is accompanied by an electric current (0.5 mA) being applied to the grid floor for 500 msec (conflict). This component is signaled by illumination of the houselight and three cue lights on the front panel. This sequence of three components (reward/time-out/conflict) are presented twice in the same order during the daily 30 minute session. Animals are given extensive training on this schedule until the following criteria had been satisfied: 1) rates of responding during the individual VI30 components do not differ by more than 10%; 2) rates of responding during time-out and conflict are less than 10% of the rate during the VI component; and 3) the above criteria are satisfied for a period of five days.
After the training procedure, drug testing is initiated. During this period, the animals are dosed orally with either test compounds or vehicle in a randomized order 60 minutes before testing. At least two drug-free training days occur between test sessions. This test indicates that the compound has anxiolytic properties which are not observed with typical antipsychotic agents. Spealman et al., J. Pharmacol. Exp. Ther., 212:435-440, 1980.
Further, the pharmacological profile of the claimed compounds is desirable for use in the treatment of other conditions which are related to the mediation of a muscarinic receptor. Such conditions include for example, Alzheimer""s Disease, glaucoma, irritable bowel syndrome, bladder dysfunction and incontinence, treatment of pain, analgesia, Huntington""s Disease, epilepsy, Parkinson""s Disease, anxiety, and other psychotic conditions as described in the DSM-IV.
While it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the invention. Such compositions contain from about 0.1 percent by weight to about 90.0 percent by weight of a present compound. As such, the present invention also provides pharmaceutical formulations comprising a compound of the invention and a pharmaceutically acceptable excipient therefor.
In making the compositions of the present invention, the active ingredient is usually mixed with an excipient which can be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium), and soft and hard gelatin capsules.
The compounds of the invention may be delivered transdermally, if desired. Transdermal permeation enhancers and delivery systems, including patches and the like, are well known to the skilled artisan.
Examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propylhydroxy-benzoates, talc, magnesium stearate, water, and mineral oil. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The compounds of this invention may be delivered transdermally using known transdermal delivery systems and excipients. Most preferrably, a compound of this invention is admixed with permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system. Additional excipients including gelling agents, emulsifiers, and buffers may be added to the transdermal formulation as desired.
For oral administration, a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to about 500 mg or more, usually about 5 to about 300 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier.